Identification, Characterization and Initial Hit-to-Lead Optimization of a Series of 4-Arylamino-3-Pyridinecarbonitrile as Protein Kinase C theta (PKCθ) Inhibitors

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• 作者：Derek C. Cole ; Magda Asselin ; Agnes Brennan ; Robert Czerwinski ; John W. Ellingboe ; Lori Fitz ; Rita Greco ; Xinyi Huang ; Diane Joseph-McCarthy ; Michael F. Kelly ; Matthew Kirisits ; Julie Lee ; Yuanhong Li
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：October 9, 2008
• 年：2008
• 卷：51
• 期：19
• 页码：5958-5963
• 全文大小：189K
• 年卷期：v.51,no.19(October 9, 2008)
• ISSN：1520-4804

文摘

The protein kinase C (PKC) family of serine/threonine kinases is implicated in a wide variety of cellular processes. The PKC theta (PKCθ) isoform is involved in TCR signal transduction and T cell activation and regulates T cell mediated diseases, including lung inflammation and airway hyperresponsiveness. Thus inhibition of PKCθ enzyme activity by a small molecule represents an attractive strategy for the treatment of asthma. A PKCθ high-throughput screening (HTS) campaign led to the identification of 4-(3-bromophenylamino)-5-(3,4-dimethoxyphenyl)-3-pyridinecarbonitrile 4a, a low μM ATP competitive PKCθ inhibitor. Structure based hit-to-lead optimization led to the identification of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-ylamino)-3-pyridinecarbonitrile 4p, a 70 nM PKCθ inhibitor. Compound 4p was selective for inhibition of novel PKC isoforms over a panel of 21 serine/threonine, tyrosine, and phosphoinositol kinases, in addition to the conventional and atypical PKCs, PKCβ, and PKCζ, respectively. Compound 4p also inhibited IL-2 production in antiCD3/anti-CD28 activated T cells enriched from splenocytes.